Day # 54: Lithium (part 3) -> Side Effects and Toxicity.

Welcome back to our current theme of bipolar disorder. Today will be the last day of our three part series about lithium. Previously, we discussed evidence + indications and levels + interactions + lab monitoring. Today we will wrap up the conversation about lithium with side effects, toxicity, and management of these symptoms.

Today’s Content Level: All levels (Beginner, Intermediate, Advanced)

SIDE EFFECTS

•We will break up the side effects into -> common side effects, serious side effects, and lithium toxicity.

Common side effects include:

• GI (nausea, vomiting, diarrhea): Diarrhea associated with higher serum drug concentrations (SDC). Taking with food decreases GI side effects. May also consider initial dosing strategy of dosing multiple small IR formulation.

• Sedation: Commonly sedating particularly during the early phase of treatment and may wear off with time. Consider night time dosing.

• Tremor: Commonly a fine symmetric hand tremor. Can present at any time during treatment. Caffeine worsens the tremor. Considering decreasing alcohol intake and doses of antipsychotic or SSRI. Can use beta blockers (propranolol) to alleviate as first line but other options include primidone, benzodiazepines, and vitamin B6.

• Cognitive: Subjective slowness and/or loss of creativity. Interestingly, these complaints may be confounded by decreased mania. This is level-dependent. Consider decreasing dose and addressing confounders.

• Weight gain: This is a common reason for discontinuation. It is dose-dependent and worse in early treatment. Encourage change in diet, exercise, and decrease high calorie drinks. Additional contributor to weight gain is edema in the legs and face. Also treat other confounders such as hypothyroidism or attempt to reduce other meds that also increase weight gain.

• Polyuria/Polydipsia: i.e. excessive urination and thirst. Occurs secondary to lithium induced nephrogenic diabetes insipidus. Determine if patient is dehydrated. Consider daily dosing, sugarless gum, or oral moisturizers for thirst. If this does not go away with time, may attempt to decrease the dose or, for the expert, cautiously add a diuretic while reducing lithium dose by 50% and monitoring plasma lithium levels.

• Sexual dysfunction: Minor dysfunction. Consider phosphodiesterase inhibitor.

• Skin: Increases risk for development or exacerbation of acne, psoriasis, and alopecia. Consider lowering the dose or treatment with typical dermatological treatments.

• Leukocytosis: Typically benign elevation of white blood cell count. Of note, in psychotic disorders requiring treatment with clozapine, lithium can be used to counteract the neutropenia.

Serious side effects include:

• Nephropathy: Long-term use associated with focal nephron atrophy in addition to interstitial fibrosis. Over time gradual decrease in renal function that is typically irreversible. Increased risk with higher doses, length of treatment, older age, and prior episodes of nephrotoxicity. Consider discontinuation or, if expertise, amiloride to block lithium from entering renal principle cells.

• Thyroid dysfunction: Goiter (40-50%), Hypothyroidism (more common, 20-30%) or hyperthyroidism (rare). Lithium inhibits thyroid hormone release. Increased risk if +antithyroid antibodies, woman, older age, or family history. Usually occurs within the first 2 years of treatment. Treat with thyroxine and does not justify discontinuation, however may be reversible if lithium is discontinued.

• Hypercalcemia: Increases absorption of calcium in the kidneys which stimulates the release of parathyroid hormone (PTH). Serum PTH concentration should be assessed in patients on lithium therapy who develop hypercalcemia.

• Cardiac: May lead to cardiovascular changes such as T wave flattening/inversion (see in both long-term therapy and acute toxicity), bradycardia, or more rarely arrhythmias such as sinus node dysfunction v-tach and v-fib.

• Neuro: in addition to the aforementioned tremor and cognitive slowing sometimes ataxia or dysarthria can be seen.

• Teratogenic: In utero exposure during the 1st trimester increases risk of cardiac malformations (classically tested is the Ebstein’s anomaly which is characterized by the displacement of the tricuspid valve and leads to the "atrialization" of the right ventricle). The absolute risk is low with evidence that the risk has been historically overestimated.

MANAGING LITHIUM SIDE EFFECTS

Potential strategies include:

• Wait, wait, wait.

• Lower the dose or lower amount of doses received per day.

• Change to a different lithium preparation such as a controlled release.

• Take entire dose at night as long as efficacy persists all day long with this schedule.

• For GI side effects -> Take with food.

• For tremor-> avoid caffeine and consider treating with propranolol.

• Attempt augmenting strategies or switching to another agent.

• Discontinue immediately if signs of lithium toxicity occur (see below).

CONTRAINDICATIONS

Lithium is contraindicated in patients with severe:

• Kidney impairment

• Cardiovascular disease

• Brugada syndrome (type of ventricular arrhythmia)

• Sodium depletion or dehydration

• Proven allergy to Lithium

• Relatively contraindicated in patients with psoriasis

LITHIUM TOXICITY

•Lithium has a very narrow therapeutic window. There is a small difference between therapeutic effect and toxicity. Lithium requires close monitoring of serum levels due to this narrow therapeutic range and lithium can be lethal in overdose. Typical treatment serum drug concentration (SDC) range is 0.6 - 1.2 mEq/L.

"Mild" Toxicity

• Typically SDC >1.5

• GI -> Anorexia, nausea, vomiting, diarrhea. Acute lithium toxicity more commonly associated with these GI effects.

• Neuro-> Drowsiness, confusion, ataxia, coarse tremor. Chronic toxicity is better characterized by these neuro effects.

Severe Toxicity

• Typically SDC > 2

• Neuro-> Altered mental status, neuromuscular hyperactivity, hyperreflexia, seizures, coma, death.

Risk factors

• Hyponatremia or low-salt diet

• Dehydration

• Drug interactions (ACE inhibitors, diuretics, NSAIDs)

• Decreased renal function

• Older age

Treatment

• Stop current lithium treatments.

• Intravenous fluids -> facilitate lithium clearance and restore sodium and water balance. Closely monitor serum sodium levels during treatment.

• Consider whole bowel irrigation with polyethylene glycol if awake and asymptomatic.

• Hemodialysis for severe toxicity. Indications include SDC >4 or SDC >2.5 with altered mental status, seizures, renal insufficiency, or heart failure (can't do fluid resuscitation).

CONCLUSION

You did it! You completed the three part series about lithium. We will continue our discussion of mood stabilizers during our next post as we cover valproic acid.

Resources for today's post include the Maudsley Prescribers Guide, Stahl's Essentials for Psychopharmacology, and Pocket Psychiatry.

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